1. Field of the Invention
The present invention relates to anti-cancer agents, and particularly to substituted spirooxindoles that inhibit p53-MDM2 interaction.
2. Description of the Related Art
Cancer is a major cause of morbidity and mortality, with approximately 14 million new cases and 8 million cancer-related deaths in 2012, affecting populations in all countries and all regions. These estimates correspond to age-standardized incidence and mortality rates of 182 and 102 per 100 000, respectively.
Much recent cancer research has focused on the p53-MDM2 loop. The p53 protein, often referred to as a tumor suppressor, has been linked to transcription of proteins that mark cancer cells for cell death. Nevertheless, p53 levels that are too high may mark normal cells for cell death. The levels of p53 in a cell are regulated by the protein MDM2. Coincidentally, the expression of MDM2 protein in the cell is the result of activation of the MDM2 gene by p53 itself. The mechanism by which MDM2 regulates p53 levels is related to the conformation of the MDM2 protein, which has folds defining a deep cleft that define a binding site for the N-terminal end of the p53 protein. Actual binding has been linked to four pairs of amino acids in p53 and MDM2 that bond to each other. Uncontrolled growth of cancerous tumors has been correlated with elevated levels of MDM2, leading to over-suppression of p53 in at least some cancers. For example, the overexpression of MDM2 has been observed in a wide range of tumor types, including brain (11%), breast (5-40%), soft tissue tumors (17%).
Consequently, one proposed strategy is to identify pharmaceutical agents that will inhibit p53-MDM2 interaction by selectively binding to the site in the MDM2 protein that normally binds the p53 protein in order to elevate p53 levels. Macromolecules and long chain proteins are not suitable because they cannot fit into the deep cleft where the binding site is located. Hence, the focus has been on small molecules. Several selective small-molecule inhibitors have been previously reported that block the MDM2-p53 protein-protein interaction and activation of p53 as a potential cancer therapeutic strategy. Although some of the inhibitors have been spirooxindole-containing compounds, there is still a need to identify further selective small-molecule inhibitors with anti-cancer activity and other attractive biological activities for pharmacological use in the treatment of cancer.
Thus, substituted spirooxindoles solving the aforementioned problems are desired.